Oral pretreatment with <i>Escherichia coli</i> Nissle 1917 enhances the host's defense against influenza A virus infection

Influenza A viruses (IAVs) pose a significant threat to global health, causing annual epidemics and occasional pandemics with substantial morbidity and mortality. Despite the availability of vaccines and antiviral therapies, the development of novel preventive and therapeutic strategies remains a critical research focus. In this study, we evaluated the protective effects of orally administering <i>Escherichia coli</i> Nissle 1917 in IAV-infected mice and elucidated its mechanisms of action by analyzing cecal microbiota and plasm metabolome profiles. Oral administration of <i>E. coli</i> Nissle 1917 alleviated respiratory symptoms, reduced weight loss, and mitigated pathological injury in mice infected with H9N2 or H1N1 IAV. These protective effects were mediated through the modulation of gut microbiota diversity, which increased the abundance of <i>Bacteroides</i> and <i>Akkermansia</i>, correlating with elevated pipecolic acid levels and ultimately aiding in defense against IAV infection in mice. Notably, we identified that the circulating metabolic molecule pipecolic acid plays a significant role in fighting IAV infection. Our findings suggest the potential usefulness of <i>E. coli</i> Nissle 1917 or pipecolic acid in influenza prevention.